Researchers in the School of Medicine and several other centers around the United States will soon begin recruiting patients to continue studying a potential treatment for Crohn’s disease, a chronic and serious inflammatory disease of the gastrointestinal tract that affects about a half-million people in the United States.
A preliminary study published last fall in The Lancet reported that enhancing the body’s innate immunity can improve symptoms of Crohn’s disease in 80 percent of patients with moderate to severe forms of the debilitating disorder.
Earlier this month, Joshua Korzenik, M.D., assistant professor of medicine in the Division of Gastroenterology, presented preliminary data from a recently completed multicenter trial at an American College of Gastroenterology meeting. That study began almost two years ago and followed 124 patients with moderate-to-severe Crohn’s disease at 33 centers throughout the United States.
Some received an inactive placebo. Others were given daily injections of a drug called GM-CSF (granulocyte macrophage colony stimulating factor), which stimulates the activity of certain cells in the immune system. In the past, GM-CSF was used primarily in patients undergoing chemotherapy for leukemia.
Crohn’s disease has always been considered the result of an overactive immune system, so most therapies have attempted to suppress the body’s immune response. But the studies of GM-CSF have looked at whether revving up part of the immune system can relieve symptoms.
A typical Crohn’s patient regularly deals with diarrhea, abdominal pain and intra-abdominal infections. Frequently, the disease closes off sections of the intestine, and patients need surgery to eliminate blockages.
Korzenik is leaving in November to go to Massachusetts General Hospital, but he has spent his time at the University working with Brian Dieckgraefe, M.D., Ph.D., also an assistant professor of medicine in the Division of Gastroenterology. Although they no longer will work at the same medical center, the two are committed to maintaining a long-distance collaboration.
“We work very well together,” Korzenik said. “Brian is primarily in basic science. I’m in clinical science, and our ideas grew out of discussions between us as we thought about how we might be able to help patients with Crohn’s disease, because so many don’t get relief from current treatments.”
Dieckgraefe started out working with gene chips, conducting studies to find genes turned on and off in Crohn’s disease. Initially, those studies weren’t much help because in patients with Crohn’s disease, the immune response is so revved up that many genes are activated.
So Dieckgraefe took a step backward, and the research effort began to concentrate on genetic events that might occur before most symptoms appear.
Because Crohn’s disease was thought to result from an impaired immune response, they looked at other genetic diseases that also impair immunity.
“There are probably 20 different mutations that lead to impaired immunity,” Dieckgraefe explained. “They affect a part of the immune system called innate immunity — first-line cells that launch initial attacks on bacteria and other microbes.”
The researchers looked at two disorders in particular: glycogen storage disease 1B and chronic granulomatous disease.
Dieckgraefe reasoned that by learning how these genetic disorders shut down innate immunity, they might be able to mimic some of those genetic mutations and changes. In theory, that might make it possible to use gene therapy to impair immune response, thereby helping Crohn’s disease patients.
At least that’s how the project started. But the studies of patients with impaired immunity yielded some startling findings.
“Much to our surprise, we found that in some of these immune disorders, patients develop a clinical illness that is indistinguishable from Crohn’s disease,” Dieckgraefe said. “These people had impaired immune systems, and they had Crohn’s disease, too.”
Was it possible, they wondered, that the conventional thinking on Crohn’s disease was incorrect? Maybe the immune system only became overactive as a way to compensate for a weak response earlier. What would happen to Crohn’s disease symptoms if these patients with genetic immune diseases were treated with drugs that actually enhanced their innate immune response?
The answer to that question was already out there. In 1991, two drugs became routinely available in the United States to help correct impaired immunity in these patients. One of them was GM-CSF. The other is a similar drug called G-CSF (granulocyte colony stimulating factor). Both drugs used natural proteins to jump-start innate immunity and help patients live with their immune system disorders.
Dieckgraefe and Korzenik also learned that when those patients with rare immune system disorders took the drugs, their Crohn’s disease symptoms went away.
They decided it might be worthwhile to look at treating Crohn’s disease by stoking up the body’s innate immunity, rather than impairing it.
“At first blush, the idea of priming the immune system in patients with Crohn’s disease sounds sort of like throwing oil on a fire,” Korzenik said. “You might compare it to proposing a high cholesterol diet to treat heart disease.”
Oddly enough, it appears to work. Patients in both the initial study and the recently-completed multicenter trial took daily injections of GM-CSF, also known by the trade name Leukine (sagramostim), and most got better. But maintenance trials showed that Crohn’s disease symptoms returned when patients stopped taking the drug.
Based on those preliminary results, Berlex Laboratories Inc. — the pharmaceutical firm that owns Leukine — initiated the large-scale, multicenter study that just concluded.
Because those results also were positive, the company is launching another study as part of an effort to petition the Food and Drug Administration for approval of GM-CSF as a treatment for Crohn’s disease.